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| Phil Seo, M.D.
Treatment Pathophysiology Clinical Aspects | ||
| Treatment | ||
Abstract 601: No Additional Steroid Sparing Effect of Cyclosporin A in Patients with Giant Cell Arteritis Background: Giant cell arteritis is a large-vessel vasculitis that can have multiple manifestations, including jaw or upper extremity claudication, polymyalgia rheumatica, fever of unknown origin, and visual loss. Standard therapy for giant cell arteritis utilizes a prolonged course of high-dose glucocorticoids, which have numerous undesirable effects, such as cataracts, avascular necrosis, osteoporosis, hyperglycemia, and mood disorders. Because of the numerous side-effects associated with glucocorticoids (e.g., prednisone), there has been great interest in identifying immunosuppressive agents that might decrease the total amount of glucocorticoid needed to bring this disease under control. This abstract reports the results of a multicenter European trial of 58 patients with biopsy-proven giant cell arteritis randomized to receive adjunctive therapy with cyclosporine A. Study Design: Patients were treated with a standardized glucocorticoid regimen starting with 40 mg of oral prednisone daily for 1 week. Half of these patients were randomized to receive treatment with low dose cyclosporine A, titrated to a goal dosage of 3mg/kg/day. Patients were evaluated at baseline, and 1, 2, 4, 6, 9, and 12 months after enrollment. Results: At 12 months, there was no significant difference in the median daily dose of prednisone or the median cumulative dose of prednisone. Patients in both groups experienced a similar number of flares and complete remissions. Intolerance to cyclosporine A was significant; 11 patients randomized to receive therapy with cyclosporine A withdrew, either due to side effects or unspecified non-compliance with the study drug. Editorial Comments: Ironically, the elderly patients who are the most likely to develop giant cell arteirtis are also the least likely to tolerate the high doses of glucocorticoids that it requires. Methotrexate has been studied in two large randomized controlled trials of giant cell arteritis with mixed results, although it may still be a reasonable second-line agent in patients with refractory disease. Similarly, cyclosporine A does not seem to have a dramatic effect on the outcomes in this disease. A large, industry-sponsored, randomized-controlled trial of infliximab as an adjunctive therapy for giant cell arteritis has recently completed enrollment, and this may eventually represent a viable alternative for patients with this disease. | ||
Abstract 602: High Dose Pulse Intravenous Glucocorticoid Infusion as the Initial Treatment of Giant Cell Arteritis Background: The most feared complication of ginat cell arteritis is visual loss, generally the result of anterior ischemic optic neuropathy. Therefore, when the possibility of giant cell arteritis is raised, clinicians generally start therapy with glucocorticoids immediately. Even with aggressive therapy, however, visual loss for some patients is inevitable. Because of the enormous impact that visual loss has on quality of life, many clinicians are inclined to treat patients with visual symptoms from giant cell arteritis with intravenous pulse glucocorticoids, even in the absence of solid data supporting this approach. This abstract reports the results of a double-blind, randomized controlled trial of patients with giant cell arteritis randomized to receive therapy with pulse glucocorticoids. Study design: This trial enrolled 27 patients with biopsy-proven giant cell arteritis, 14 of whom were initially treated with intravenous methylprednisolone 15mg/kg daily for three days. Patients in the placebo arm received normal saline intravenously during the same period of time. Patients were simultaneously treated with prednisone 40 mg daily for two weeks, followed by a pre-defined tapering regimen designed to have patients off glucocorticoids by week 34. The primary endpoint was the number of patients taking 5 mg or less of prednisone within the first 34 weeks of therapy. Relapse was defined as return of signs or symptoms associated with giant cell arteritis, or an increase in C-reactive protein. Results: Patients were followed for 18 months on average; one patient in each arm was lost to follow-up. Among patients treated with intravenous glucocorticoids, 71.4% reached the primary endpoint, as opposed to only 15.4% of patients in the treatment arm. There were 34 flares of giant cell arteritis in the placebo group, but only 21 flares among patients initially treated with intravenous glucocorticoids. The median cumulative dose of oral prednisone was 7215 mg in the placebo group, but only 4852 mg in the intervention group. Finally, at 18 months, 0 patients in the placebo group and 6 patients in the intervention group were in remission (which was defined as being off of glucocorticoids for 2 months or greater). There was no difference in the incidence of osteoporosis, osteopenia, hypertension, hyperlipidemia, hyperglycemia, or avascular necrosis between the two groups. Editorial Comments: Initial treatment of patients with intravenous pulses of glucocorticoids is not considered standard therapy for giant cell arteritis. This small trial, however, convincingly demonstrates that patients who are initially treated aggressively are more likely to be tapered off glucocorticoids and less likely to experience relapse than those treated with oral glucocorticoids alone. Interestingly, this approach did not diminish the impact of several of the untoward effects associated with glucocorticoids. Patients enrolled in this study will continue to be followed for a total of 3 years; it will be interesting to see if the benefits noted in this abstract persist with time. | ||
Abstract 1719: The Wegener's Granulomatosis Etanercept Trial: Randomized Double-Masked, Placebo-Controlled Trial of Etanercept for the Induction and Maintenance of Remission Background: Wegener's granulomatosis is a multisystem inflammatory illness that involves the upper and lower respiratory tracts, and is often characterized by the presence of antineutrophil cytoplasmic antibodies (ANCA). The treatment of Wegener's granulomatosis with glucocorticoids and cyclophosphamide is associated with both treatment-related morbidity and a high rate of relapse. To date, there is no regimen that leads to safe, durable disease remissions. There is strong evidence that tumor necrosis factor (TNF) is important to the pathogenesis of granulomatous diseases. Thus, it is logical to believe that anti-TNF therapy may be able to play an important role in the treatment of Wegener's granulomatosis. This abstract reports the results of a multicenter, double-blind, placebo-controlled study of patients receiving standard immunosuppressive therapy who were randomized to receive adjunctive therapy with either etanercept or placebo. Study Design: Patients with active Wegener's granulomatosis were stratified by disease severity and clinical center. Patients were followed until the last patient enrolled had been treated for 1 year. Patients received methotrexate or cyclophosphamide, depending on the severity of the underlying disease, and glucocorticoids according a standardized taper designed to have patients completely off glucocorticoids by 6 months. Patients with renal insufficiency were treated with azathioprine instead of methotrexate. The primary outcome was sustained remission (defined as a Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) of 0 for 6 months or longer). Results: One hundred eighty patients were enrolled in this trial, 89 of whom were randomized to receive treatment with etanercept in addition to standard-of-care therapy. Ninety percent of patients in both groups achieved disease remission. The primary outcome of sustained remission was achieved by 70% of patients in the etanercept group and 85% of patients in the control group. This difference was not statistically significant (p=0.39). Time to sustained remission, number of flares, and number of severe flares were statistically equivalent in both groups. Although approximately of patients achieved disease remission, only remained in remission for the length of the trial. Of note, 6 solid tumor malignancies occurred in the etanercept group, but none occurred in the control group. Editorial Comments: The results of this trial may very well represent the end of TNF-inhibitors as a therapy for patients with ANCA-associated vasculitis. It should be noted that this trial employed an etanercept dosage of 25 mg twice weekly, and therefore does not eliminate the possibility that a higher dose (or a different TNF inhibitor) might be more efficacious. The resoundingly negative results of this trial, however, will likely dampen enthusiasm for pursing this line of therapy. Case series indicate that infliximab may be efficacious, but is associated with a high rate of infection. Finally, the increased risk of malignancy is intriguing, although it is too early to say if that increased risk will remain with longer periods of follow-up. | ||
Abstract 605: Rituximab for Remission Induction in Severe ANCA-associated Vasculitis. A Report of a Prospective Open-Label Pilot Trial in 10 Patients Background: Cyclophosphamide and high-dose glucocorticoids are surprisingly efficacious at inducing disease remission among patients with severe forms of ANCA-associated vasculitis (a group of diseases that includes Wegener's granulomatosis and microscopic polyangiitis). These medications, however, are associated with significant morbidity, which has prompted a search for alternate agents. The efficacy of cyclophosphamide in the treatment of these diseases may owe in part to its ability to suppress B-cell function. Rituximab is a chimeric monoclonal anti-CD20 antibody that has been used for the treatment of non-Hodgkin's lymphoma, and more recently idiopathic thrombocytopenic purpura, hemolytic anemia, and rheumatoid arthritis. This abstract reports the results of a prospective open label trial of rituximab for the treatment of patients with severe ANCA-associated vasculitis. Study Design: This is an open-label study of patients with either Wegener's granulomatosis or microscopic polyangiitis who could not be treated with standard therapy (due to contraindications or refractory disease). Patients were treated with rituximab 375 mg/m2 on days 1, 8, 15, and 21 of the trial. Patients were simulatenously treated with prednisone, initially at 1mg/kg/day, followed by a taper designed to have them off of glucocorticoids completely at the end of 6 months. The primary endpoint was clinical remission, which was defined as a BVAS/WG of 0 off glucocorticoids. Patients were eligible for retreatment if they suffered clinical relapse and their B cell population was reconstituted. Results: 7 men and 3 women with ANCA-associated vasculitis were treated with rituximab as described above. All had previously been exposed to cyclophosphamide; 3 had cyclophosphamide-refractory disease, while 7 had suffered untoward effects that precluded further use. All 10 patients achieved remission as defined above. Over 12 months of follow-up, B cell counts had returned to normal levels in 9 patients, and 5 patients required retreatment. Adverse events were limited to an increased risk of upper respiratory tract infection. Editorial Comments: This study provides promising evidence that rituximab is efficacious and well tolerated for the treatment of severe ANCA-associated vasculitis. Although retreatment seems to be inevitable for many patients, decreased exposure to glucocorticoids and cytotoxic medications still make this a tempting option. This strategy is the subject of a multicenter randomized controlled clinical trial run jointly by the Mayo Clinic and the Johns Hopkins Vasculitis Center that will start enrolling patients later this year. | ||
| Pathophysiology | ||
Abstract 603: Targets of Anti-Endothelial Cell Antibodies in Patients with Systemic Vasculitis: Identification by the Proteomic Approach Background: Anti-endothelial cell antibodies have recently been identified in several forms of vasculitis. A key step towards identifying the role that these antibodies may play in the pathogenesis of these diseases is the identification of the endothelial autoantigens against which these antibodies are formed. This abstract reports a novel approach to identifying potential autoantigens among patients with systemic vasculitis. Results: Two-dimensional electrophoresis was used to isolate proteins from immortalized human (HeLa) cells and human umbilical cord vein endothelial cells. Sera isolated from 37 patients with various forms of vasculitis (including microscopic polyangiitis, Wegener's granulomatosis, the Churg-Strauss syndrome, giant cell arteritis, polyarteritis nodosa, Takayasu's arteritis, and Behcet's disease) were used to perform differential Western blotting of proteins from these 2 sources. Proteins that were identified by anti-endothelial cell antibodies in the endothelial cell preparation, but not in the HeLa cell preparation, were considered potential targets. Using this technique, approximately 50 potential autoantigens were found. Using peptide masss fingerprinting, 7 specific proteins were identified. One of these proteins was peroxiredoxin II, an anti-oxidative enzyme that participates in regulation of the redox system. Recombinant peroxiredoxin II was recognized by serum samples from 60% of patients with various forms of systemic vasculitis, including Wegener's granulomatosis, microscopic polyangiitis, and Takayasu's arteritis, but only 4% of serum samples from control patients. Clinically, the investigators noted that patients with systemic vasculitis who also possessed anti-endothelial cell antibodies also tended to have a higher level of D-dimers, indicating a possible relationship with thrombogenesis. In some patients, degredation of anti-peroxiredoxin-II IgG antibodies occurred before or during similar declines in inflammatory markers, which may indicate a pathogenic role for these antibodies. Editorial Comments: This brief summary fails to do justice to the enormous amount of technically-challenging work represented by this abstract. It should be remembered, however, that this represents only a first step. The authors identified only 7 of 50 potential auto-antigens recognized by anti-endothelial cell antibodies. Although peroxiredoxin-II is a promising target, it is quite possible that the true target is one of the unidentified peptides. The ubiquity of this autoantibody in so many forms of vasculitis is supportive of its role as a common pathway of injury. It would be interesting to see if anti-peroxiredoxin-II antibodies are also identified in sera from patients with non-autoimmune mediated vascular injury (such as coronary artery disease), or from patients with vasculopathy (such as systemic sclerosis). Regardless, this technique represents a powerful tool for the identification of potential autoantigens, and will likely play an increasingly prominent role in rheumatology research. | ||
| Clinical Aspects | ||
Abstract 604: Association Between Disease Activity and Plasma Myeloperoxidase, CRP, WSR and ANCA in Patients with Wegener's Granulomatosis Background: The assessment of disease activity in the study of systemic vasculitis can be surprisingly challenging. When evaluating a patient with Wegener's granulomatosis, for example, it can be difficult to tell the difference between sinus disease that is the result of active inflammation, infection, or chronic damage. Because there are no reliable biomarkers for disease activity, patients may be treated overly aggressively, leading to additional exposure to immunosuppressive agents (including glucocorticoids), each of which is associated with its own morbidity. This abstract reports the results of a rigorous attempt to correlate several serologic markers with disease activity in Wegener's granulomatosis. Study Design: This study used a registry of patients diagnosed with Wegener's granulomatosis between 1994 and 2000. Patients in the registry who also had stored serum samples were eligible for this study. The Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) was applied retrospectively to patients in this study as a measure of disease activity. Results: Patients with active Wegener's granulomatosis had significantly higher titers of plasma myeloperoxidase (MPO), C-reactive protein, and erythrocyte sedimentation rate. Patients who developed active disease tended to have an increase in their MPO titer and C-reactive protein. Proteinase 3-ANCA was less useful, due to significant overlap among patients with active and inactive disease. An MPO titer of 145 pM or greater had a sensitivity of 75% and a specificity of 71% for active WG. ANCA titers were much less specific for active disease; conversely, a C-reactive protein greater than or equal to 2mg/dL had a specificity of 80% (but a sensitivity of only 63%) for active disease. Editorial Comments: MPO titers have been recognized as a marker for cardiovascular disease, and it is not surprising that they may be used as a marker of active vasculitis as well. The interpretation of a retrospective trial must necessarily be somewhat cautious, as all the markers tested are probably influenced by treatment, which likely results in changes at the molecular level well in advance of clinically apparent change. It is important to remember that the gold standard in this study was based on retrospective clinical assessment, which may also be problematic. A multifactorial analysis incorporating both CRP and MPO titers might yield even greater discriminant value, but is unlikely to supplant the role of clinical gestalt in the assessment of patients with WG. | ||
Abstract 606: Epidemiology of Primary Systemic Vasculitis-Unchanged Over 15 years Background: Most of our knowledge of the epidemiology of Wegener's granulomatosis and microscopic polyangiitis comes from Europe. Various studies have demonstrated that Wegener's granulomatosis seems to be more common in northern Europe, while microscopic polyangiitis is more common in southern Europe. Some studies indicate the occurrence of cyclical peaks, which could reflect an infectious etiology for these diseases. Other studies also note an increasing prevalence of these diagnoses. Whether this increased prevalence actually reflects an increased awareness by clinicians of these diagnoses is not clear. Study Design: This abstract presents the results of a cohort study based in Norwich and Ipswich (in the United Kingdom), which has a population of 430,000 adults. This population is both isolated and stable, and is served by a single referral center. This population has been previously well characterized for an epidemiologic study of rheumatoid arthritis. Cases were identified from outpatient and inpatient records, diagnosis codes, and histopathology records for kidney, skin, and nerve biopsies. Potential cases were then reviewed for accuracy. Patients with a clinical history of vasculitis supported by objective data (such as ANCA titer or pathology) were included in this analysis. Cases were classified using ACR and Chapel Hill consensus criteria. Results: The overall annual incidence of vasculitis in this population is 19.9 cases per million. In 1989 to 1993, the annual incidence was 20.3 cases per million. In 1999 to 2003, the annual incidence declined to 17.1 cases per million, although the difference was not statistically significant. From 1989 to 2003, the annual incidence of Wegener's granulomatosis, microscopic polyangiitis, and the Churg-Strauss syndrome remained stable (10.2, 5.8, and 4.2 cases per million, respectively). When analyzed in terms off 3-year rolling averages, there appeared to be a peak in the incidence of systemic vasculitis in the mid 1990's, followed by a steady decline over time. There was no evidence of a cyclical pattern. Editorial Comments: One of the first questions asked by patients with systemic vasculitis is what causes the disease. It is certainly reasonable to hypothesize that changing environmental factors (such as increased exposure to pesticides or changing antimicrobial spectra) might influence the prevalence of these diseases, although overall, this does not seem to be the case. It should be noted that a classic study of giant cell arteritis performed in Olmstead County, MN, did demonstrate evidence of cyclical peaks in the prevalence of this disease, which lends credence to the search for an infectious etiology for this particular form of vasculitis. | ||
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